PDBsum entry 1e3s

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Oxidoreductase PDB id
Protein chains
241 a.a. *
NAD ×4
Waters ×492
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Rat brain 3-hydroxyacyl-coa dehydrogenase binary complex with nadh
Structure: Short chain 3-hydroxyacyl-coa dehydrogenase. Chain: a, b, c, d. Synonym: hadh ii. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: brain. Organelle: mitochonria. Cellular_location: cytoplasm. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Biol. unit: Homo-Tetramer (from PDB file)
2.0Å     R-factor:   0.189     R-free:   0.226
Authors: A.J.Powell,J.A.Read,M.J.Banfield,R.L.Brady
Key ref:
A.J.Powell et al. (2000). Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD). J Mol Biol, 303, 311-327. PubMed id: 11023795 DOI: 10.1006/jmbi.2000.4139
22-Jun-00     Release date:   25-May-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O70351  (HCD2_RAT) -  3-hydroxyacyl-CoA dehydrogenase type-2
261 a.a.
241 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - 3-hydroxy-2-methylbutyryl-CoA dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD+ = 2-methylacetoacetyl-CoA + NADH
Bound ligand (Het Group name = NAD)
corresponds exactly
= 2-methylacetoacetyl-CoA
   Enzyme class 3: E.C.  - 3-hydroxyacyl-CoA dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (S)-3-hydroxyacyl-CoA + NAD+ = 3-oxoacyl-CoA + NADH
Bound ligand (Het Group name = NAD)
corresponds exactly
= 3-oxoacyl-CoA
   Enzyme class 4: E.C.  - 3(or 17)-beta-hydroxysteroid dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Testosterone + NAD(P)(+) = androst-4-ene-3,17-dione + NAD(P)H
+ NAD(P)(+)
= androst-4-ene-3,17-dione
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     mitochondrion   1 term 
  Biological process     metabolic process   6 terms 
  Biochemical function     oxidoreductase activity     11 terms  


DOI no: 10.1006/jmbi.2000.4139 J Mol Biol 303:311-327 (2000)
PubMed id: 11023795  
Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD).
A.J.Powell, J.A.Read, M.J.Banfield, F.Gunn-Moore, S.D.Yan, J.Lustbader, A.R.Stern, D.M.Stern, R.L.Brady.
Human type II hydroxyacyl-CoA dehydrogenase/amyloid-beta binding alcohol dehydrogenase (HADH II/ABAD) is an oxidoreductase whose salient features include broad substrate specificity, encompassing 3-hydroxyacyl-CoA derivatives, hydroxysteroids, alcohols and beta-hydroxybutyrate, and the capacity to bind amyloid-beta peptide, leading to propagation of amyloid-induced cell stress. In this study, we examine the structure and enzymatic activity of the homologous rat HADH II/ABAD enzyme. We report the crystal structure of rat HADH II/ABAD as a binary complex with its NADH cofactor to 2.0 A resolution, as a ternary complex with NAD(+) and 3-ketobutyrate (acetoacetate) to 1.4 A resolution, and as a ternary complex with NADH and 17 beta-estradiol to 1.7 A resolution. This first crystal structure of an HADH II confirms these enzymes are closely related to the short-chain hydroxysteroid dehydrogenases and differ substantially from the classic, type I 3-hydroxyacyl-CoA dehydrogenases. Binding of the ketobutyrate substrate is accompanied by closure of the active site specificity loop, whereas the steroid substrate does not appear to require closure for binding. Despite the different chemical nature of the two bound substrates, the presentation of chemical groups within the active site of each complex is remarkably similar, allowing a general mechanism for catalytic activity to be proposed. There is a characteristic extension to the active site that is likely to accommodate the CoA moiety of 3-hydroxyacyl-CoA substrates. Rat HADH II/ABAD also binds amyloid-beta (1-40) peptide with a K(D) of 21 nM, which is similar to the interaction exhibited between this peptide and human HADH II/ABAD. These studies provide the first structural insights into HADH II/ABAD interaction with its substrates, and indicate the relevance of the rodent enzyme and associated rodent models for analysis of HADH II/ABAD's physiologic and pathophysiologic properties.
  Selected figure(s)  
Figure 4.
Figure 4. Co-factor binding and catalytic mechanism of rHADH II/ABAD. (a) Schematic diagram showing inter- actions between NADH and rHADH II/ABAD. (b) Schematic diagram showing the proposed reaction mechanism of rHADH II/ABAD, based on structural similarity to other SDR enzymes and mechanism previously proposed for human 17b-hydroxysteroid dehydrogenase by Breton et al. (1996). The numbers adjacent to the hydrogen bonds (bro- ken lines) are the distances in angstroms measured between these groups in the respective crystal structures.
Figure 6.
Figure 6. Binding of CoA substrates to rHADH II. The Figure shows a model of the expected conformation of a bound acetoacetyl-CoA substrate. The C a trace of a single subunit of rHADH II/ABAD is shown in pale blue, with the co-factor in purple, acetoacetate group (from the crystal structure of the 3-ketobutyrate com- plex) in red, and the thioester-linked coenzyme A group in green. The two phosphate groups of the CoA moiety are labelled PA and PN, and adjacent conserved, posi- tively charged amino acid residues are also shown and labelled.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 303, 311-327) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20175748 K.E.Muirhead, E.Borger, L.Aitken, S.J.Conway, and F.J.Gunn-Moore (2010).
The consequences of mitochondrial amyloid beta-peptide in Alzheimer's disease.
  Biochem J, 426, 255-270.  
20809899 K.E.van Straaten, H.Zheng, D.R.Palmer, and D.A.Sanders (2010).
Structural investigation of myo-inositol dehydrogenase from Bacillus subtilis: implications for catalytic mechanism and inositol dehydrogenase subfamily classification.
  Biochem J, 432, 237-247.
PDB codes: 3mz0 3nt2 3nt4 3nt5 3nto 3ntq 3ntr
19204834 X.Wu, N.Liu, Y.He, and Y.Chen (2009).
Cloning, expression, and characterization of a novel diketoreductase from Acinetobacter baylyi.
  Acta Biochim Biophys Sin (Shanghai), 41, 163-170.  
18453685 M.M.Hoque, S.Shimizu, M.T.Hossain, T.Yamamoto, S.Imamura, K.Suzuki, M.Tsunoda, H.Amano, T.Sekiguchi, and A.Takénaka (2008).
The structures of Alcaligenes faecalis D-3-hydroxybutyrate dehydrogenase before and after NAD+ and acetate binding suggest a dynamical reaction mechanism as a member of the SDR family.
  Acta Crystallogr D Biol Crystallogr, 64, 496-505.
PDB codes: 2yz7 2zea 3vdq
18167351 Y.Ren, H.W.Xu, F.Davey, M.Taylor, J.Aiton, P.Coote, F.Fang, J.Yao, D.Chen, J.X.Chen, S.D.Yan, and F.J.Gunn-Moore (2008).
Endophilin I expression is increased in the brains of Alzheimer disease patients.
  J Biol Chem, 283, 5685-5691.  
16899120 A.T.Marques, A.Antunes, P.A.Fernandes, and M.J.Ramos (2006).
Comparative evolutionary genomics of the HADH2 gene encoding Abeta-binding alcohol dehydrogenase/17beta-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10).
  BMC Genomics, 7, 202.  
16633561 B.Youn, R.Camacho, S.G.Moinuddin, C.Lee, L.B.Davin, N.G.Lewis, and C.Kang (2006).
Crystal structures and catalytic mechanism of the Arabidopsis cinnamyl alcohol dehydrogenases AtCAD5 and AtCAD4.
  Org Biomol Chem, 4, 1687-1697.
PDB codes: 2cf5 2cf6
16888731 C.Feller, R.Günther, H.J.Hofmann, and M.Grunow (2006).
Molecular basis of substrate recognition in D-3-hydroxybutyrate dehydrogenase from Pseudomonas putida.
  Chembiochem, 7, 1410-1418.  
16380372 K.Guo, P.Lukacik, E.Papagrigoriou, M.Meier, W.H.Lee, J.Adamski, and U.Oppermann (2006).
Characterization of human DHRS6, an orphan short chain dehydrogenase/reductase enzyme: a novel, cytosolic type 2 R-beta-hydroxybutyrate dehydrogenase.
  J Biol Chem, 281, 10291-10297.
PDB code: 2ag5
17028273 M.Avadhani, R.Geyer, D.C.White, and L.J.Shimkets (2006).
Lysophosphatidylethanolamine is a substrate for the short-chain alcohol dehydrogenase SocA from Myxococcus xanthus.
  J Bacteriol, 188, 8543-8550.  
16927253 P.Inbar, C.Q.Li, S.A.Takayama, M.R.Bautista, and J.Yang (2006).
Oligo(ethylene glycol) derivatives of thioflavin T as inhibitors of protein-amyloid interactions.
  Chembiochem, 7, 1563-1566.  
15653677 B.Youn, S.G.Moinuddin, L.B.Davin, N.G.Lewis, and C.Kang (2005).
Crystal structures of apo-form and binary/ternary complexes of Podophyllum secoisolariciresinol dehydrogenase, an enzyme involved in formation of health-protecting and plant defense lignans.
  J Biol Chem, 280, 12917-12926.
PDB codes: 2bgk 2bgl 2bgm
15513927 D.J.Hosfield, Y.Wu, R.J.Skene, M.Hilgers, A.Jennings, G.P.Snell, and K.Aertgeerts (2005).
Conformational flexibility in crystal structures of human 11beta-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation.
  J Biol Chem, 280, 4639-4648.
PDB codes: 1xu7 1xu9
16215233 L.Carlisle-Moore, C.R.Gordon, C.A.Machutta, W.T.Miller, and P.J.Tonge (2005).
Substrate recognition by the human fatty-acid synthase.
  J Biol Chem, 280, 42612-42618.  
15531764 M.S.Alphey, W.Yu, E.Byres, D.Li, and W.N.Hunter (2005).
Structure and reactivity of human mitochondrial 2,4-dienoyl-CoA reductase: enzyme-ligand interactions in a distinctive short-chain reductase active site.
  J Biol Chem, 280, 3068-3077.
PDB codes: 1w6u 1w73 1w8d
15860413 S.Y.Yang, X.Y.He, and H.Schulz (2005).
Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase.
  Trends Endocrinol Metab, 16, 167-175.  
15770646 S.Yoon, A.Smellie, D.Hartsough, and A.Filikov (2005).
Computational identification of proteins for selectivity assays.
  Proteins, 59, 434-443.  
15087549 J.W.Lustbader, M.Cirilli, C.Lin, H.W.Xu, K.Takuma, N.Wang, C.Caspersen, X.Chen, S.Pollak, M.Chaney, F.Trinchese, S.Liu, F.Gunn-Moore, L.F.Lue, D.G.Walker, P.Kuppusamy, Z.L.Zewier, O.Arancio, D.Stern, S.S.Yan, and H.Wu (2004).
ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
  Science, 304, 448-452.
PDB code: 1so8
15236401 K.Tieu, C.Perier, M.Vila, C.Caspersen, H.P.Zhang, P.Teismann, V.Jackson-Lewis, D.M.Stern, S.D.Yan, and S.Przedborski (2004).
L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson's disease.
  Ann Neurol, 56, 51-60.  
12524453 J.K.Yang, M.S.Park, G.S.Waldo, and S.W.Suh (2003).
Directed evolution approach to a structural genomics project: Rv2002 from Mycobacterium tuberculosis.
  Proc Natl Acad Sci U S A, 100, 455-460.
PDB codes: 1nff 1nfq 1nfr
12906824 N.Manoj, E.Strauss, T.P.Begley, and S.E.Ealick (2003).
Structure of human phosphopantothenoylcysteine synthetase at 2.3 A resolution.
  Structure, 11, 927-936.
PDB code: 1p9o
12192068 C.A.Bottoms, P.E.Smith, and J.J.Tanner (2002).
A structurally conserved water molecule in Rossmann dinucleotide-binding domains.
  Protein Sci, 11, 2125-2137.  
12419215 C.W.Carter, and W.L.Duax (2002).
Did tRNA synthetase classes arise on opposite strands of the same gene?
  Mol Cell, 10, 705-708.  
12006485 D.H.Fong, and A.M.Berghuis (2002).
Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry.
  EMBO J, 21, 2323-2331.
PDB codes: 1l8t 1l8u 2b0q
11496149 N.G.Milton, N.P.Mayor, and J.Rawlinson (2001).
Identification of amyloid-beta binding sites using an antisense peptide approach.
  Neuroreport, 12, 2561-2566.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.